Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
Relay Therapeutics, Cambridge, MA, USA.
Nat Struct Mol Biol. 2020 Jun;27(6):540-549. doi: 10.1038/s41594-020-0416-6. Epub 2020 May 4.
Amyloid appearance is a rare event that is promoted in the presence of other aggregated proteins. These aggregates were thought to act by templating the formation of an assembly-competent nucleation seed, but we find an unanticipated role for them in enhancing the persistence of amyloid after it arises. Specifically, Saccharomyces cerevisiae Rnq1 amyloid reduces chaperone-mediated disassembly of Sup35 amyloid, promoting its persistence in yeast. Mathematical modeling and corresponding in vivo experiments link amyloid persistence to the conformationally defined size of the Sup35 nucleation seed and suggest that amyloid is actively cleared by disassembly below this threshold to suppress appearance of the [PSI] prion in vivo. Remarkably, this framework resolves multiple known inconsistencies in the appearance and curing of yeast prions. Thus, our observations establish the size of the nucleation seed as a previously unappreciated characteristic of prion variants that is key to understanding transitions between prion states.
淀粉样外观是一种罕见的事件，它在其他聚集蛋白的存在下得到促进。这些聚集物被认为通过模板形成组装能力的成核种子起作用，但我们发现了它们在增强淀粉样物质形成后的持久性方面的意外作用。具体来说，酿酒酵母 Rnq1 淀粉样蛋白降低了伴侣介导的 Sup35 淀粉样蛋白的解聚，促进了其在酵母中的持久性。数学建模和相应的体内实验将淀粉样蛋白的持久性与 Sup35 成核种子的构象定义大小联系起来，并表明淀粉样蛋白通过低于此阈值的解聚被主动清除，以抑制体内 [PSI] 朊病毒的出现。值得注意的是，该框架解决了酵母朊病毒出现和消除过程中的多个已知不一致问题。因此，我们的观察结果确定了成核种子的大小是朊病毒变体的一个以前未被认识到的特征，这是理解朊病毒状态之间转变的关键。
